The overall survival for non-small cell lung cancer (NSCLC) is about 16%, whereas for SCLC, overall survival is 6%. Jemal et al., CA Cancer J. Clin., (2007), 57, 43-66. Overcoming resistance of lung cancer to either chemo-radiotherapy or epidermal growth factor receptor (EGFR) targeted therapy would provide to be a significant achievement. B-cell lymphoma 2 protein (Bcl-2) is a member of the Bcl-2 family of apoptosis regulator proteins. Bcl-2 is extensively expressed in various types of cancer, including lung cancer, leukemia, breast cancer, prostatic cancer, pancreatic cancer, head/neck cancer, etc. One major factor implicated in the resistance of cancer to chemotherapy is the overexpression of Bcl-2 and Bcl-2-like proteins. The BH4 domain of Bcl-2 has been demonstrated to be a required domain for Bcl-2's anti-apoptotic function, which is associated with increased chemo-resistance of cancers. Bcl-2 is extensively expressed in both SCLC and NSCLC cells.
EGFR has been identified as an important therapeutic target for the treatment of NSCLC because more than 60% of NSCLC patients express EGFR. EGFR inhibition by EGFR-tyrosine kinase inhibitors (TKIs) (i.e. erlotinib or gefitinib) represents a promising approach for lung cancer therapy. Unfortunately, patients who initially benefited from erlotinib therapy developed acquired resistance to erlotinib after 6-12 months. The mechanisms are not fully understood but may be associated with activation of EGFR-independent pathways, occurrence of additional EGFR gene mutations or loss of the target.
In addition to acting as an antiapoptotic protein, Bcl-2 can also promote tumor angiogenesis. Under hypoxia Bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. See Trisciuoglio et al., Cell Death and Differentiation (2011), 1-12. Mutations at the BH4 domain abrogate the ability of Bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells and other human tumor histotypes, such as colon, ovarian and lung carcinomas. BH4 peptide is sufficient to increase HIF-1α protein half-life impairing HIF-1α protein ubiquitination and enhance VEGF secretion in melanoma cells exposed to hypoxia.
HIF-1 alpha is overexpressed in many tumor types including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. See abstract of Zhong et al., Cancer Res., 1999, 59(22):5830 entitled “Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.” See also Semenza, Intern Med., 2002, 41(2):79-83 entitled “Involvement of hypoxia-inducible factor 1 in human cancer;” Zhong et al., Biochem Biophys Res Commun., 2001, 284(2):352-6 entitled “Hypoxia-inducible factor 1alpha and 1beta proteins share common signaling pathways in human prostate cancer cells;” Pugh et al., Breast Cancer Res., 2001, 3(5):313-7 entitled “Hypoxia and oxidative stress in breast cancer. Hypoxia signalling pathways;” and Giatromanolaki et al., Br J Cancer., 2001, 85(6):881-90 entitled “Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival.”
Certain diaminoanthraquinone derivatives are angiogenesis inhibitors and have been proposed as potential anticancer drugs. See Takano et al., Journal of Pharmacology and Experimental Therapeutics, (1994), 271(2), 1027-33. See also U.S. Pat. Nos. 6,465,522, 5,733,880, 5,436,243, and 5,344,841.